Project Summary/Abstract The persistent problem of weight regain following weight loss is perhaps the most significant barrier to addressing the current obesity epidemic. The biological drive to regain weight following weight loss is due in part to increased appetite leading to increased energy intake (EI) and reductions in energy expenditure (EE) in part due to changes in energy expended in physical activity (PA). These physiological adaptations to weight loss are most relevant during episodes of dietary indiscretion resulting in overfeeding (OF) when reduced obese (RO) people fail to respond to the state of positive energy balance in a way that maintains the reduced state. There is increasing evidence that RO individuals who exercise (RO-Ex) are less likely to regain as compared to RO individuals who are sedentary (RO-Sed). We conducted studies on the effects of OF on EI, EE, PA and fat metabolism in non-obese individuals either prone (OP) or resistant to obesity (OR). Subjects were then followed for 5 years to measure weight change. These studies showed that differences in the response of nocturnal fat oxidation and higher levels of moderate/vigorous PA following OF correlated with 5 year weight gain suggesting that these factors were potentially important mechanisms for weight gain. Further we have shown that measures of hunger fail to suppress with OF in RO individuals and that nocturnal fat oxidation is reduced in RO-Sed but maintained in RO-Ex following a day that included a bout of exercise. We now propose to study the responses of EE, EI, PA and fat metabolism to OF (40% above basal energy for 3 days) in obese, RO-Sed and RO-Ex men and women and correlate these responses to weight change over the subsequent year. We hypothesize that changes in the response of one or more of these variables to OF will correlate with weight regain. The Significance of the studies lies in the fact that they will begin to clarify the metabolic mechanisms that underlie a propensity for weight regain in RO individuals. Innovation: The proposed studies will systematically examine a range of responses to OF and prospectively correlate them with weight gain while taking into account aspects of behavior relevant to weight regain. We believe that these studies will lay a foundation for future studies that will examine the mechanisms underlying specific adaptive responses that directly relate to weight regain and help with the design of strategies to address and/or respond to these processes.